2. Academic Validation
  3. Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone

Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone

  • Cell Chem Biol. 2020 Mar 19;27(3):292-305.e6. doi: 10.1016/j.chembiol.2020.01.008.
Jay K Singh 1,  Darren M Hutt 1,  Bradley Tait 2,  Naihsuan C Guy 3,  Jeffrey C Sivils 3,  Nina R Ortiz 3,  Ashley N Payan 3,  Shravan Kumar Komaragiri 4,  Jazzmin Jovonna Owens 4,  David Culbertson 5,  Laura J Blair 6,  Chad Dickey 6,  Szu Yu Kuo 7,  Dan Finley 8,  H Jane Dyson 5,  Marc B Cox 3,  Jaideep Chaudhary 4,  Jason E Gestwicki 7,  William E Balch 9
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 2 Brad Tait Enterprise LLC, 80 Christian Way, North Andover, MA 01845, USA.
  • 3 Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79902, USA.
  • 4 School of Arts and Sciences, Clark Atlanta University, Atlanta, GA 30314, USA.
  • 5 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 6 Department of Molecular Medicine and Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL 33613, USA.
  • 7 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
  • 8 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 9 Department of Molecular Medicine, Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: webalch@scripps.edu.
PMID: 32017918 DOI: 10.1016/j.chembiol.2020.01.008
Abstract

HSP90 plays an important role in health and is a therapeutic target for managing misfolding disease. Compounds that disrupt co-chaperone delivery of clients to HSP90 target a subset of HSP90 activities, thereby minimizing the toxicity of pan-Hsp90 inhibitors. Here, we have identified SEW04784 as a first-in-class inhibitor of the Aha1-stimulated HSP90 ATPase activity without inhibiting basal HSP90 ATPase. Nuclear magnetic resonance analysis reveals that SEW84 binds to the C-terminal domain of Aha1 to weaken its asymmetric binding to HSP90. Consistent with this observation, SEW84 blocks Aha1-dependent HSP90 chaperoning activities, including the in vitro and in vivo refolding of firefly luciferase, and the transcriptional activity of the Androgen Receptor in cell-based models of prostate Cancer and promotes the clearance of phosphorylated tau in cellular and tissue models of neurodegenerative tauopathy. We propose that SEW84 provides a novel lead scaffold for developing therapeutic approaches to treat proteostatic disease.

Keywords

Aha1; Alzheimer disease; androgen receptor (AR); heat shock protein 90 (Hsp90); prostate cancer; tau.

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